Compositions and methods for joining non-conjoined lumens

ABSTRACT

Disclosed are compositions, methods, and kits for joining together non-conjoined lumens in a patient&#39;s body including vascular lumens. More particularly, in various aspects, this invention provides compositions, methods, and kits for joining such non-conjoined lumens, including small lumens typically requiring microsurgical technique.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application of U.S. patentapplication Ser. No. 11/766,779, now U.S. Pat. No. 8,216,259, filed Jun.21, 2007, which claims the benefit under 35 U.S.C. §119(e) ofprovisional Patent Application Ser. Nos. 60/805,425, filed on Jun. 21,2006, 60/806,242, filed on Jun. 29, 2006, and 60/914,635, filed on Apr.27, 2007, all of which are incorporated herein by reference in theirentirety.

FIELD OF THE INVENTION

This invention relates generally to compositions, methods, and kits forjoining together non-conjoined lumens in a patient's body includingvascular lumens. More particularly, in various aspects, this inventionprovides compositions, methods, and kits for joining such non-conjoinedlumens, including small lumens typically requiring microsurgicaltechniques.

BACKGROUND OF THE INVENTION

Non-conjoined lumens arise in a variety of settings including surgicalsettings where the non-conjoined lumens are intentionally created orthose arising from lacerations or puncture wounds. Intentionally creatednon-conjoined lumens include those arising during surgical repair ofe.g., treatment of a blockage in a lumen by bypass procedures, attachinga synthetic graft or during free tissue transfer in cosmetic surgicalsettings. Anastomosis is conducted to surgically reconnect the open endsof the lumen. Examples of anastomosis procedures include anastomoticprocedures on the vasculature, the vas deferens, the fallopian tubes,the urinary tract, tear ducts, bowel, mammary glands, alimentary ducts,pancreatic ducts, bile ducts, etc. In each case, the anastomosisprocedure creates a channel for the flow of a body fluid there through.

The anastomosis may, for example, be end-to-end, end-to-side, andside-to-side. As is apparent from their names, anastomosis may involvevarious configurations. For instance, one tubular tissue may be joinedside-to-end with two tubular tissues, creating a three-channeled tubulartissue construct.

In the surgical context, end-to-end anastomosis, as is apparent from itsname, is a surgical procedure for connecting an end or distal portion ofone tubular tissue structure to an end or distal portion of anothertubular tissue structure, such that a continuous lumen is created. (Asused herein, “end” or “distal portion,” refers to the open end of thetubular tissue.)

In an end-to-side anastomosis, a tubular tissue structure having a holeor open part is connected through the open part to an open or distal endof a tubular tissue to form a continuous lumen with a branchedconfiguration. Similarly, in a side-to-side anastomosis, twonon-conjoined lumens are merged together into a continuous lumen thougha hole or opening on each of the lumens to be joined.

A successful anastomosis typically involves the smooth connection oflumens, such that the internal structure is not blocked and internalbody fluid flow—such as blood, semen or food or gastrointestinalfluids—is restored or improved. Ideally, the matching up/ligationsurgical procedure is rapid and precise, so that patient exposure whilein a vulnerable state—such as having blood flow stopped—is minimized.

There are a variety of “tubular tissues”, and the lumen of the firsttubular tissue may not be of the same diameter as the lumen of thesecond tubular tissue. Thus, because the delicate surgery may involvematching and ligating two (or more) non-identical tubular tissues,various ligation techniques have been used with varying rates ofsuccess. These include sutures, tissue adhesives, adhesive strips, andstaples, clips and other devices. To some extent all of these materialsinvolve the skill of the practitioner in anastomosis which is accurate,durable and free from conditions which could cause latent deleteriousreactions in vivo.

The labor-intensive needle and thread remains the most-used technologyas of the present day. Because of the complexity and judgment requiredin suturing, automated techniques are not well accepted. Calcified anddiseased vessels provide mechanical challenges. Sutures may, in someinstances, cause a reaction resulting in long term stenosis or fibrosis.

Other approaches to anastomosis include the use of sealants and biogluesfor ligation. These may be used individually or in conjunction withsuturing or other mechanical ligation techniques or devices. Forexample, one commercially available sealant CoSeal® (AngiotechPharmaceuticals, Inc., Vancouver, B.C., Canada) may complement suturingin cardiovascular surgeries.

Mechanical anastomosis devices, such as clips, are also available. Onecommercially available device, the U-Clip™ (Medtronic, Minneapolis,Minn. 55432 USA), essentially provides a sharp, nitinol hook forknotting to compete anastomosis. The nitinol allows reversibledeformation. The C-Port® (Cardica, Inc. Redwood City, Calif. 94063 USA)and related products are commercially available and use miniaturestainless steel staples to securely attach the bypass graft to thecoronary artery.

Before ligating end-to-end (for example), the practitioner must match upthe lumens by the circumference of the vessel (using blood vessels as anillustration). Frequently, this is troublesome to the practitionerbecause the end of an tubular tissue—such as a clamped blood vesseldevoid of blood—is not a perfectly round circle; rather it is in itsunpressurized, deflated-looking state where a cross-sectional view ofthe circumference may be a circle, an oval or irregular, and, of coursehaving no structural support from within, is unstably in any shape(unless the surrounding tissue possesses structural strength). The sizeof the vessels to be connected may also be different. Although bloodvessels (for example) or other tubular tissues are somewhat elastic(deformable and returning to the original shape) or plastic (deforming,and not fully returning to the original shape), connecting thecircumferences of the lumens such that upon ligation there is no orminimal leakage (in the vascular context, for example), requires askilled practitioner.

In a microvascular context, anastomosis is performed between ends ofblood vessels in the course of, for example, reattaching severed bodyparts or transplanting organs or tissues. Microvascular anastomosis isoften performed by hand under a microscope, and is tedious andpainstaking work. The blood vessels connected together often havedifferent diameters, both of which are very small, on the order of about1 to about 5 millimeters (“mm”). Although blood vessels are usually atleast somewhat elastic, the practitioner must match up end to end (forexample) two different shaped-different-sized circumferences and thenstitch them together (for example). As a result, it can take many hoursto complete just the microvascular anastomosis required to reconnect asevered body part or transplant an organ.

One attempt to provide a mechanism for performing such a microvascularanastomosis is the Microvascular Anastomotic Coupler System, availablefrom Bio-Vascular, Inc. (San Diego, Calif., USA). In this mechanism, anend of each vessel to be connected is essentially turned outward(“everted”) over a ring with a forceps or similar instrument. Each ringincludes a number of pins over which the vessel is everted. The ringsare then pressed together, such that the pins on each ring enterrecesses in the other ring, connecting the rings and holding the ends ofthe vessels together. This system, however, is limited to use with twoblood vessels having substantially the same diameter. Further, manualeversion of a blood vessel having a diameter on the order of onemillimeter is difficult and painstaking, particularly when the eversionis to be substantially even around the circumference of the ring.Further, the rings provide a noncompliant anastomosis between the twovessels. Thus, although stabilizing the circumference facilitates theability of the practitioner to match up vessels for end-to-endmicrovascular anastomosis, the device requires, essentially,practitioners skilled in microsurgical techniques.

For patients and practitioners, perhaps the most demanding anastomosisis incident to heart revascularization. The arteries that bring blood tothe heart muscle (coronary arteries) can become clogged by plaque (abuildup of fat, cholesterol and other substances). This can slow or stopblood flow through the heart's blood vessels, leading to chest pain or aheart attack. Increasing blood flow to the heart muscle can relievechest pain and reduce the risk of heart attack. A patient may undergoone, two, three or more bypass grafts, depending on how many coronaryarteries are blocked.

Coronary artery bypass graft surgery (“CABG”, sometimes pronounced“cabbage” by practitioners) reroutes, or “bypasses,” blood aroundclogged arteries to improve blood flow and oxygen to the heart. Inperforming the CABG anastomosis, a segment of a healthy blood vesselfrom another part of the body is used to make a detour around theblocked part of the coronary artery. This healthy blood vessel may be,for example, an artery present in the thoracic cavity, or may be a pieceof a long vein from the patient's leg. In some circumstances, graftsfrom non-autologous sources may be used, such as synthetic tubulartissues or animal tubular tissues. Regardless of the source of thehealthy blood vessel, one end is connected to the large artery leavingthe patient's heart (the aorta), and the other end is attached or“grafted” to the coronary artery below the blocked area. In this way of“rewiring” the vasculature, substantially unobstructed blood flow to theheart muscle is resumed.

Conventionally, a pump oxygenator (heart-lung machine) is used forcoronary bypass graft operations. Medicines are used to stop thepatient's heart, which allows the practitioner to operate without theheart beating. The heart-lung machine keeps oxygen-rich blood movingthroughout the patient's body. For this conventional heart bypass graftsurgery, a team of practitioners is needed (a surgeon, cardiacanesthesiologist and surgical nurse, and a perfusionist (blood flowspecialist)). Multiple practitioners, additional complexity, and, as apractical matter, additional health care cost is involved over surgicalprocedures involving fewer practitioners and procedures.

Moreover, blood quality may be degraded as the heart-lung machinerepetitively pumps the patient's blood through the systemic circulation.The blood may embolize or clot in the distal circulation, or form clotswhich migrate to the distal vasculature, and cause a stroke.

“Off Pump” coronary artery bypass grafting, also called beating heartbypass grafting, takes place while the heart continues to beat, but amechanical device may be used in an attempt to steady the surroundingvasculature, so that the practitioner can perform the graft. Off pumpcoronary artery bypass surgery may reduce this risk. Frequently, becausethe graft must be performed on arteries in locations directly affectedby the beating heart, stabilizing mechanisms are not thoroughlyeffective, and the practitioner must suture the graft while the graft ismoving in conjunction with the heart beat, at least to some extent.Thus, the graft quality may be compromised.

Although, in a bypass surgery time is of the essence, the practitionercannot rush through without thoroughly and precisely anastomising thegraft(s). In conventional coronary artery bypass surgery, three criticaldeterminates that affect the outcome of a bypass surgery are:

-   -   (1) time the patient spends on cardiopulmonary bypass,    -   (2) time the patient spends with a clamped aorta, and    -   (3) the quality of the anastomosis.

After an hour, the risk of patient morbidity is thought to increaseperhaps due to the heart-lung machine degrading the quality of the bloodas it is circulated through the systemic circulation. Bypass surgeries,however, often last three hours or longer. Moreover, where the aorta isclamped and blood therefore cannot pass through, the blocked blood isthought to cause additional issues.

Anastomosis is time-consuming. The average time for suturing oneanastomosis is approximately fifteen to sixty minutes. An average CABGprocedure is thought to involve approximately five anastomoses.Therefore, the average time for graft suturing exceeds the sixty-minutethreshold for increased patient morbidity. Patients treated withconventional coronary surgery and placed on cardiopulmonary bypass wouldbenefit from reducing the amount of time spent performing eachanastomosis.

In “off pump” procedures where the heart remains beating, the difficultyof suturing an anastomosis graft on a moving surface of the heart maydegrade the quality of such grafts completed on patients. An anastomosisdiffers from straight line suturing in that each suture has a differentorientation that is based on its position around the cross-sectionalcircumference of the blood vessel graft. It can be appreciated that someof the sutures are easily made from on top of the conduit or bloodvessel graft, while others are more difficult to complete as they arebeneath the conduit. It can be further appreciated that performing suchcomplex suturing procedures on a moving platform, such as the beatingheart, further increases the difficulty associated with such suturingprocedures. Improperly connecting blood vessel grafts to the patient maypresent substantial post-operative complications and/or increaseoperating room time spent correcting the improperly connected graft.

Accordingly, for surgical anastomosis, both practitioners and patientswould benefit from faster procedures allowing patients to minimizeprocedure time, and simpler methods allowing reduced complexity and easeof use and higher quality anastomosis with fewer complications.

SUMMARY OF THE INVENTION

This invention is directed to the discovery that the stabilization ofthe geometry of the terminal portions of tubular tissues facilitatesjoining such non-conjoined tissues. In one aspect, such stabilization isachieved by use of biocompatible solid materials which can be placedinto the terminal portions of at least one of the lumens of the tubulartissues to be joined.

Thus, in one aspect, this invention relates to a method for joining atleast two non-conjoined lumens in a patient which method comprises:

-   -   a) providing a biocompatible solid mass in at least the distal        portion of at least one of the lumens;    -   b) aligning the lumens;    -   c) joining the aligned lumens to form a conduit; and    -   d) removing the solid mass thereby establishing flow through the        conduit.

In one embodiment, the solid mass is placed in the distal portion(opening) of each lumen to be joined. In another embodiment, the solidmass is placed in the distal portion of a first lumen in a manner inwhich the solid mass protrudes from the distal portion such that thisprotrusion can be used as a male mating functionality with the distalportion of the second lumen which acts as a female mating functionality.

The biocompatible solid mass employed in the methods described herein isnot critical provided that it imparts sufficient structural integrity tothe distal portion of the lumen. Examples of suitable solid massesinclude sol-gel solutions, waxes, thixotropic agents, etc.

The joining of the lumens may be accomplished by applying abiocompatible adhesive, suturing, or applying laser, such as laserwelding or laser soldering.

The removal of the solid mass can be accomplished using any of a numberof physical properties of the mass such as melting, phase change, changein viscosity, dissolution in the body fluid and/or combinations of theseproperties.

Accordingly, in another of its method aspects, there is provided amethod for joining at least two non-conjoined lumens having distal(open) ends, comprising the steps of:

-   -   providing a phase-reversible sol-gel inside at least a portion        of the distal end of the first lumen in a manner which imparts        structural integrity to said portion of the first lumen;    -   providing a phase-reversible sol-gel inside at least a portion        of the distal end of a second lumen in a manner which imparts        structural integrity to said portion of the second lumen;    -   aligning the distal portions of the first and second lumens;    -   joining said lumens so as to provide for a conduit;    -   inducing a phase change in the phase-reversible sol-gel in said        conduit wherein said sol-gel phase changes to a liquid phase;        and    -   allowing flow through said conduit.

In still another of its method aspects, there is provided a method forjoining at least two non-conjoined lumens having distal (open) ends,comprising the steps of:

-   -   providing a phase-reversible sol-gel inside at least a portion        of the distal end of a first lumen in a manner which imparts        structural integrity to said portion of the first lumen wherein        said sol-gel protrudes from the distal end;    -   mating the distal end of a second lumen with said protrusion        from the first lumen thereby aligning the first and second        lumens;    -   joining said lumens so as to provide for a conduit;    -   inducing a phase change in the phase-reversible sol-gel in said        conduit wherein said sol-gel phase changes to a liquid phase;    -   allowing flow through said conduit.

In another of its method aspects, there is provided a method for joiningat least two non-conjoined lumens in a patient which method comprises:

-   -   (a) providing a biocompatible phase-reversible sol-gel        composition in at least the distal portion of at least one of        the lumens in a manner which imparts structural integrity to        said portion of the lumen or lumens;    -   (b) aligning the lumens;    -   (c) closing the aligned lumens to form a conduit; and    -   (d) removing the sol-gel composition thereby establishing flow        through the conduit;    -   wherein the phase-transition of the sol-gel composition is        triggered by an stimulus selected from a change in temperature,        a change in pH, a change in ionic strength, a change in        pressure, a change in electric field, a change in magnetic        field, a change in electron magnetic radiation, a change in        light or ultraviolet light, a change in concentration, a change        in osmolarity, and combinations thereof.

In some embodiments using a sol-gel composition, the step of providingthe sol-gel composition in the lumen comprises:

-   -   placing the phase-reversible sol-gel in a gel phase inside at        least a portion of the distal end of at least one of the lumens        in a manner which imparts structural integrity to said portion        of the lumen.

In some embodiments using a sol-gel composition, the step of providingthe sol-gel composition in the lumen comprises:

-   -   placing the phase-reversible sol-gel in a liquid phase inside at        least a portion of the distal end of at least one of the lumens;        and    -   inducing a phase transition change in the phase-reversible        sol-gel in the lumen wherein the liquid phase changes to a gel        phase which imparts structural integrity to said portion of the        lumen.

In some embodiments, the method further comprises a step before the stepof providing the sol-gel composition in the lumen, which step comprisesarresting the flow of body fluid in the lumens.

In another of its method aspects, there is provided a method for joiningat least two non-conjoined lumens having distal (open) ends, comprisingthe steps of:

-   -   providing a solid biocompatible wax inside at least a portion of        the distal end of the first lumen in a manner which imparts        structural integrity to said portion of the first lumen;    -   providing a solid biocompatible wax inside at least a portion of        the distal end of a second lumen in a manner which imparts        structural integrity to said portion of the second lumen;    -   aligning the distal portions of the first and second lumens;    -   joining said lumens so as to provide for a conduit; and    -   converting the wax from a solid to a dissolved and/or liquid        form such that flow is established through said conduit.

In still another of its method aspects, there is provided a method forjoining at least two non-conjoined lumens having distal (open) ends,comprising the steps of:

-   -   providing a solid biocompatible wax inside at least a portion of        the distal end of a first lumen in a manner which imparts        structural integrity to said portion of the first lumen which        wax protrudes from said distal end;    -   mating the distal end of a second lumen with said protrusion        from the first lumen thereby aligning the first and second        lumens;    -   joining said lumens so as to provide for a conduit; and    -   converting the wax from a solid to a dissolved and/or liquid        form such that flow is established through said conduit.

In another of its method aspects, there is provided a method for joiningat least two non-conjoined lumens having distal (open) ends, comprisingthe steps of:

-   -   providing a solid biocompatible thixotropic agent inside at        least a portion of the distal end of the first lumen in a manner        which imparts structural integrity to said portion of the first        lumen;    -   providing a solid biocompatible thixotropic agent inside at        least a portion of the distal end of a second lumen in a manner        which imparts structural integrity to said portion of the second        lumen;    -   aligning the distal portions of the first and second lumens;    -   joining said lumens so as to provide for a conduit; and    -   converting said thixotropic agent from a solid to a dissolved        and/or liquid form such that flow is established through said        conduit.

In still another of its method aspects, there is provided a method forjoining at least two non-conjoined lumens having distal (open) ends,comprising the steps of:

-   -   providing a solid biocompatible thixotropic agent inside at        least a portion of the distal end of a first lumen in a manner        which imparts structural integrity to said portion of the first        lumen which agent protrudes from said distal end;    -   mating the distal end of a second lumen with said protrusion        from the first lumen thereby aligning the first and second        lumens;    -   joining said lumens so as to provide for a conduit; and    -   converting said thixotropic agent from a solid to a dissolved        and/or liquid form such that flow is established through said        conduit.

In still another of its method aspects, there is provided a method ofconnecting ducts within a living mammal, comprising the steps of:

-   -   providing a phase-reversible gel inside a first hollow duct in a        manner which holds the first duct open; providing a        phase-reversible gel inside a second hollow duct in a manner        which holds the second duct open;    -   applying adhesive between an end of the first duct and an end of        the second duct and allowing the adhesive to form bonds between        the first and second ducts;    -   inducing a phase change in the phase-reversible gel inside the        first duct and inside the second duct; and    -   allowing flow through the first duct to the second duct.

In some embodiments, the adhesive is further placed on the out surfaceof both ducts to join them together.

This invention is also directed to novel compositions useful in themethods described above. For example, in one embodiment, this inventionis directed to thermoreversible compositions having a transitiontemperature of between 0° C. and 45° C.

In one embodiment, the thermoreversible sol-gel comprises:

-   -   a) a biocompatible polymer and    -   b) water;    -   wherein the thermoreversible so-gel has a sol-gel transition        temperature of from about 35° C. to 42° C. and a modulus of from        at least about 100 to about 500,000 Pascals.

In another embodiment, the thermoreversible sol-gel has a sol-geltransition temperature of between 15° C. and 35° C. and a modulus offrom at least about 100 to about 500,000 Pascals.

In another embodiment, the thermoreversible sol-gel has a modulus offrom at least about 8,000 Pascals.

In one embodiment, the polymer is a block co-polymer of polyoxyethyleneand polyoxypropylene or mixtures of such block copolymers. In anotherembodiment, the composition is sterile.

In another embodiment, the sol-gel composition that is a gel or solid ata temperature below the transition temperature and a liquid above thetransition temperature.

In another aspect, the thermoreversible sol-gel further comprises abiocompatible protein which increases the phase transition temperatureof the composition while the structural integrity of the sol-gel modulusin the gel state.

In still another embodiment, the solid mass may contain a biocompatibledye so as to facilitate the alignment of the first and second lumen.

This invention is also directed to novel kits useful in the methodsdescribed above. In one embodiment, the kit comprises a deliveringdevice; and a composition selected from a sol-gel, a wax, and athixotropic material. In another embodiment, the kit further comprisesat least one clamp for closing at least one of the non-conjoined lumen.In still another embodiment, the kit further comprises a biocompatibleadhesive for sealing the lumens.

The present invention also includes use of any of the materials ormethods as disclosed herein for manufacture of a medicament for joininglumens, particularly in a live patient, as further described herein.Thus, in one embodiment, the present invention provides a biocompatiblesolid mass for use in joining at least two non-conjoined lumens in apatient in a method which comprises:

-   -   a) placing the a biocompatible solid mass in at least the distal        portion of at least one of the lumens;    -   b) aligning the lumens;    -   c) closing the aligned lumens to form a conduit; and    -   d) removing the solid mass thereby establishing flow through the        conduit.

In another aspect, the invention is directed to a vessel of acardiovascular system of a mammal, wherein the vessel has aphase-reversible sol-gel composition positioned in the vessel in amanner and in an amount sufficient to hold walls of the vessel open in afashion similar to when blood flows through the vessel, wherein thephase-transition of the sol-gel composition is triggered by anenvironment condition selected from a change in temperature, a change inpH, a change in ionic strength, a change in pressure, a change inelectric field and combinations thereof.

The methods, compositions and kits of this invention may be used in bothhuman and non-human mammals.

These and other embodiments of the invention are further described inthe text that follows.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is best understood from the following detailed descriptionwhen read in conjunction with the accompanying drawings. It isemphasized that, according to common practice, the various features ofthe drawings are not to-scale. On the contrary, the dimensions of thevarious features are arbitrarily expanded or reduced for clarity.Included in the drawings are the following figures:

FIG. 1 is a schematic cross-sectional view of a tubular tissue with apartial blockage.

FIG. 2 is a schematic cross-sectional view of the tubular tissue of FIG.1 wherein the area having the partial blockage has been removed creatingtwo non-conjoined lumens having both ends of the tubular tissue clampedoff.

FIG. 3 is a schematic cross-sectional view of the tubular tissue of FIG.1 with one end filled with thermoreversible sol-gel (solid or gel phase)and the other end being filled with the sol-gel (liquid phase) via asyringe.

FIG. 4 is a schematic cross-sectional view of the tubular tissue of FIG.1 with the ends sealed, the gel (solid phase) in place and the clampsstill present.

FIG. 5 is a schematic cross-sectional view of the tubular tissue of FIG.1 with the ends sealed, the sol-gel (reversed to liquid phase) in placeand the clamps removed.

FIG. 6 is a cross-sectional view of the tubular tissue of FIG. 1 showingthe sol-gel dissolved and flow restored with the blockage area removed.

FIG. 7 is a graph of a triblock polymer versus temperature with noprotein and three different concentrations of protein added.

FIG. 8 is a graph of the effect of heparin delivered with poloxamer ascompared with heparin delivered directly.

DETAILED DESCRIPTION OF THE INVENTION

Before the present compositions, medical systems, kits, and methods aredescribed, it is to be understood that this invention is not limited toparticular embodiments described, as such may, of course, vary. It isalso to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto be limiting, since the scope of the present invention will be limitedonly by the appended claims.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “athermoreversible gel” includes a plurality of such gels and reference to“the adhesive” includes reference to one or more adhesives andequivalents thereof known to those skilled in the art, and so forth.

I. Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. As used herein the followingterms have the following meanings. If not defined, a term has its artrecognized meaning.

The term “patient” refers to mammals and includes humans and non-humanmammals.

The term “surgical” relates to any medical procedure where the innerorgan or issue of a patient is accessed to investigate and/or treat apathological condition such as disease or injury, to help improve oralter bodily function or appearance, or for other reasons. As usedherein, “surgical” relates to procedures of accessing a patient's innerorgan or tissue via an incision or an opening on the patient and vianeedle-puncture of the skin, such as in percutaneous approaches andother minimally invasive procedures, such as laparoscopic surgeries.

The term “lumen” refers to the hollow tube and the surrounding tissuedefining the hollow tube, such as a blood vessel, a vas deferens, afallopian tube, urinary tract, a tear duct, bowel, a mammary gland, analimentary duct, a pancreatic duct, a bile duct, and the like. The term“lumen” is used interchangeably with the term “duct.”

The term “biocompatible” as used with terms such as “biocompatiblepolymer”, “biocompatible compound” and the like, refer to materialswhich, in the amounts employed, are non-toxic and substantiallynon-immunogenic when used internally in a subject such as a humanpatient.

The term “biocompatible solid mass” refers to a biocompatible masshaving sufficient structural rigidity to maintain the shape of thefilled lumen (i.e. impart structure integrity) during joining of thedistal opening of the lumens and which solid mass can be subsequentlyremoved from the joined lumens so as to permit flow there through.Examples of biocompatible solid masses include sol-gel compositions,waxes, thixotropic agents, and the like. In a preferred embodiment, thesolid mass has a modulus of from about 100 to 500,000 Pascals or a yieldstress of about 100 to 500,000 Pascals for the thixotropic solid mass.More preferably, the solid mass has a modulus or a yield stress of fromabout 8,000 to 50,000 or 10,000 to 50,000 Pascals and, still morepreferably, from about 12,000 to 40,000 Pascals.

The term “distal end” and “opening” of a lumen are used interchangeablyherein and refer to the opening of the lumen, for example, the two endscreated when a lumen is surgically divided into two parts. “Distal end”or “opening” also refers to a hole cut on part of the wall of a lumenalthough the lumen is not completely divided, as in the case of anend-to-side or side-to-side anastomosis.

The term “distal portion of the lumen” refers to the portion of thelumen adjacent to the opening in the lumen. Thus, for example, when alumen is surgically cut, the resulting two openings define the distalportion of what are now first and second lumens. Distal portion of thelumen also refers to the portion adjacent to the hole of a lumen to beused in an end-to-side or side-to-side anastomosis procedure. Insurgical procedures where a clamp is employed on each of thenon-conjoined lumens, the distal portion is the portion from the clampto the end of the open lumen.

The term “joining” refers to any method wherein the first and secondlumens are structurally joined together including by way of example,suturing, use of biocompatible glues, etc. In a preferred embodiment,joining of the lumens is conducted under conditions where there islittle or no leakage of body fluid from the juncture of the joinedlumens.

The term “removing the solid mass” refers to any of a number ofphysiological or chemical means or combinations thereof to remove thesolid mass from the conduit formed by the joined lumens. For example,the solid mass may be removed by melting as in the case of waxes havinga melting point at or slightly above body temperature. Alternatively,the solid mass may be soluble in the body fluid when flow is restored inthe joined lumens. Still further, a combination of melting anddissolution can be used. Thixotropic agents will significantly reducetheir viscosity in the presence of shear forces and become fluid innature. As such, in this case, removing the solid mass of a thixotropicagent can involve either internally applied shear such as that arisingfrom restoring flow or externally applied shear. Sol-gel compositionsundergo a phase transfer from a solid to a liquid under defined phasetransfer triggers such as temperature, pH or other ion concentration,light, ultrasound, pressure, etc. In such cases, conventional triggersare employed to effect phase transfer from a solid to a liquid. Thesolid mass may dissolve in the body fluid. Such liquids will beengrained in the body fluid and become part of the systemic flow of thatfluid until removed by the body.

The term “sol-gel” refers to a composition, typically polymeric, which,upon a defined trigger, undergoes a phase transition from a flowablecomposition with a viscosity of less than 2000 Pascal-seconds (“liquid”)to a gel or relatively solid form with a viscosity of greater than10,000 Pascal-seconds (“gel” or “solid”) which transition is preferablybut not necessarily reversible. As is well known in the science ofrheology, complex viscosities of compositions are reported inPascal-seconds and all viscosities reported in this application arereported as complex viscosities. When reversible, the composition isreferred to as a “phase-reversible sol-gel”. Preferably reversing phasefrom a solid to a liquid occurs in less than 5 minutes, more preferablyin less than 2 minutes and even more preferably in less than 1 minute.

The term “trigger” or “stimulus” refers to the environmental conditionthat triggers the phase transition from sol to gel or vise versa. Suchtriggers may include a change in temperature, a change in pH, a changein ionic strength, a change in pressure, a change in electric field, achange in magnetic field, a change in electron magnetic radiation, achange in light or ultraviolet light, a change in concentration, achange in osmolarity, and combinations thereof. One embodiment of thisinvention comprises an aqueous-based solution or compound having lowviscosity at physiological conditions, but exhibiting rapid gelation atconditions slightly outside of (e.g., ±2% to ±10%) physiologicalconditions. In the case of temperature as a stimulus, the transitionfrom a liquid state to gelled state may occur at temperatures that areslightly outside (e.g., ±2% to ±10%) physiological temperatures. Suchtemperatures are referred to as “near” the normal physiological bodytemperature. The flowable liquid solution gels in response to one ormultiple in-situ environmental stimuli, and may be reversible. Thecomposition should have biocompatibility with the host tissue. Theinvention is preferably carried out with a composition which iscomprised only of biocompatible materials and more preferably materialsapproved by regulatory agencies

“Thermoreversible sol-gel” refers to a composition that undergoes aphase transition from a liquid flowable material to a solid or gel likematerial when the temperature is raised to or above a transitiontemperature, and undergoes a phase transition from a solid or gel likematerial to a liquid flowable material when the temperature is loweredto or below the transition temperature. Such phase-transition isreversible.

Although the working example herein is a thermoreversible sol-gelcomposition, using temperature to initiate phase-transition, othersol-gel compositions systems may be similarly used, and may be selectedwith regard to the particular anastomosis use. For example, the phasechange may be due to other stimuli such as pH, ion concentration (e.g.,a change in calcium ion concentration or ionic strength), light,pressure, ultrasound, electric field, magnetic field, electronmagneticradiation, osmolarity, solvent composition, a change in theconcentration of the composition, and a combination thereof.

The sol-gel compositions may be deployed in either a substantially solidor substantially liquid state. Although the terms “substantially solid”and “substantially liquid” are relative with respect to each other, inthe context of anastomoses where the utility lies, in part, instructural support for the geometry of the terminus of a tubular tissue,“substantially solid” is used herein to mean that the sol-gel issufficiently stiff to provide such structural support; “substantiallyliquid” is used herein to mean that the sol-gel is insufficiently solidto provide such structural support.

For example, where tubular tissue is very narrow, a practitioner maywish to deploy the sol-gel via injection, as presented in further detailherein.

The terms “adhesive”, “surgical adhesive”, “glue”, “biocompatible glue”and the like are used interchangeably herein. These terms are used todescribe compounds which are or can be used in binding one tissue toanother tissue. The glue may operate by the formation of covalent bondsand allow the tissues to contact each other and naturally heal or growtogether. The adhesive may be comprised of a cyanoacrylate-basedadhesive, a fibrin-based adhesive, a polyurethane-based adhesive, apolyisocyanate-based adhesive. The polyurethane-based adhesive mayinclude a foaming agent added to produce an open cell geometry uponcuring in situ to promote tissue ingrowth. Adhesive materials may befound within publications known to those skilled in the art andreference made to U.S. Pat. No. 7,044,982 issued May 16, 2006 and U.S.Pat. No. 6,939,364 issued Sep. 6, 2005. Both of which are incorporatedherein by reference along with the publications cited therein todisclose and describe surgical adhesives to the extent that thesedisclosures do not contradict the present disclosure.

II. Solid Mass Compositions

Sol-Gel Composition Moieties

A variety of sol-gel compositions are known in the art, and have variousphase transition properties. One will appreciate that various propertiesmay be altered by changing the constituents or constituent ratios in anysol-gel. Persistence properties and mechanical properties may bealtered, including the degree to which the present sol-gels liquefy orsolidify, the nature or range of phase-transition initiation orstimulus, the persistence and the mechanical properties. The sol-gelmay, for example, include particulate materials which may increase thepersistence, as further described herein.

The following references disclose processes or compounds useful in thisart: U.S. Pat. No. 5,525,334; U.S. Pat. No. 5,702,361; U.S. Pat. No.5,695,480; U.S. Pat. No. 5,858,746; U.S. Pat. No. 5,589,568. Dumortieret al., “A Review of Polexamer 407” Pharmaceutical Research, Vol. 23,No. 12 (December 2006). T. G. Park and A. S. Hoffman, “Synthesis,Characterization, and Application of pH/Temperature-sensitiveHydrogels”, Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 17(1990), pp. 112 113. G. Chen and A. S. Hoffman, “Graft Copolymers ThatExhibit Temperature-induced Phase Transitions Over a Wide Range of pH”,Vol. 3, Nature, 1995, pp. 49 52. S. Beltran, J. P. Baker, H. H. Hooper,H. W. Blanch and J. M. Prausnitz, “Swelling Equilibria for WeaklyIonizable, Temperature-Sensitive Hydrogels”, Proc. Amer. Chem. Soc.,1991. J. Zhang and N. A. Peppas, “Synthesis and Characterization of pH-and Temperature-Sensitive Poly(Methacrylic acid)/Poly(Nisopropylacrylamide) Interpenetrating Polymeric Networks,Macromolecules, 2000 (currently available on-line on the world wideweb). T. G. Park, “Temperature Modulated Protein Release FrompH/Temperature Sensitive Hydrogels; Biomaterials 20 (1999), pp. 517-521.

Examples of sol-gel compositions include biocompatible ethylene oxidepropylene oxide co-polymers which are typically prepared as blockcopolymers and are otherwise known as poloxamer or by their tradenamessuch as Pluronics® or Lutrol®, Polyethylene-polypropylene glycol;Polyoxyethylene-Polyoxypropylene Block Copolymer; Poly(Ethyleneoxide-co-Polypropylene oxide), Block; BlockCopolymer of Ethylene Oxideand Propylene Oxide and other names. Examples of poloxamers includepoloxamer 118, poloxamer 182, poloxamer 188, poloxamer 237, poloxamer338, poloxamer 407, other block polymers that can be used in the sol-gelcomposition include poloxamines, under the tradename Tetronic®, such asTetronic® 1107, Tetronic® 1307, which are ethylene oxide and propyleneoxide based tetra-functional block copolymers. Such polymers arecommercially available from a number of sources and can be made byconventional synthetic methods. Other examples of biocompatible sol-gelcompositions include, without limitation, block copolymers ofpolyethylene glycol with a polymer selected from polyester,poly(lactide-co-glycolide), poly(α-hydroxy acids) and poly(ethylenecarbonates), described in U.S. Pat. Nos. 7,018,645, 6,004,573 and5,702,717; poly N-substituted (meth)acrylamides, described in U.S. Pat.No. 5,525,334; modified polysaccharides, such as hyaluronic acid, andothers described in U.S. Pat. No. 6,018,033; and copolymers described inU.S. Pat. No. 7,160,931. All of the references are incorporated byreference in their entirety.

In one embodiment, the thermoreversible sol-gel comprises a polymerselected from the group consisting of poloxamer 118, poloxamer 188,poloxamer 338, poloxamer 407, Tetronic® 1107 and Tetronic® 1307 or amixture thereof, and an aqueous solvent. An aqueous solvent may be wateror a water based solution, e.g. an aqueous salt solution, such as asaline solution, phosphate buffered saline, etc suitable for dissolvingthe polymers.

In some embodiments, the polymer or polymers are present in an amount ofabout 5% to about 35% by weight.

In some embodiments, the polymer or polymers are present in an amount ofabout 15% to about 20% by weight.

The molecular weight of the polymer in the sol-gel composition may be inthe range of about 8,000 to 16,000, more preferably 10,000 to 16,000, ormore preferably 10,000 to 14,000 and most preferably about 12,600. Theterm “about” as used in this context reflects that commercialpreparations of the monomers or polymers as described herein may containmixtures of varying molecular weights incident to the commercialmanufacturing process.

It is contemplated that the transition temperature of a thermoreversiblesol-gel composition should be in a range that is tolerable by the organsor tissues of the patient, such as between 0° C. and 45° C. As morefully described herein, the thermo-inducible phase transition may bealtered by the addition of a polypeptide or a protein; as such, ifproteins are added for biological activity (such as a protein havingtherapeutic effect), the practitioner will note that thephase-transition property of the underlying polymer may be altered.Alternatively, the protein may be added to effect a change in transitiontemperature of a composition otherwise having the requisite modulus.Such proteins are non-therapeutic and preferably non-immunogenic. In oneembodiment, the protein is albumin such as BSA or HSA. Recombinantversions of such proteins (or any proteins as described herein) may bepreferred for commercial manufacturing reasons, for assurance of noanimal-originating pathogenic agents.

Phase-reversible sol-gel compositions whose phase transition istriggered by other stimuli, such as pH, ionic strength, electricalfield, magnetic field, electromagnetic field, osmolarity, solventcomposition, light, ultraviolet light, pressure, chemical composition,concentration, and combinations thereof can also be used in the methodsof the invention. Examples of such sol-gel compositions are describedin, e.g., U.S. Pat. No. 5,252,318 (Joshi et al), U.S. Pat. No. 5,939,485(Bromberg et al), and US patent publications 2004/0096508 (Gutowska etal), US 2004/0213756 and 2004/0208845 (both by Michal et al), which areincorporated by reference in their entirety. For Example, chitosansolutions which undergoes a phase transition at a pH of about 7.0, andcompositions that undergo phase transition when triggered by at leasttwo stimuli are described therein. Dilution of the composition canfacilitate phase transition in certain cases.

Other compositions useful as the solid mass in this invention include avariety of hydrogels, which are water-insoluble three-dimensionalnetworks that formed by the cross-linking of water-soluble monomers.Either synthetic or natural polymers may be used. Useful syntheticmaterials are poly(lactic acid) (PLA), poly(glycolic acid) (PGA), andtheir copolymers, poly(lactic co glycolic acid) (PLGA). Suchcompositions are well known in the art.

In situ cross linking (and/or polymerization) can be used to form thegel or to increase rigidity. Therefore, for anastomosis of anindividual, the crosslinking is able to take place under physiologicconditions. Particularly for human uses, physiological conditionsinvolve a temperature of about 37° C., and a pH of about 7.4. Suitablecross linking conditions will be chosen based on the chemical structureof the monomers to be polymerized, the desired mechanical andpersistence properties of the hydrogel after polymerization, and otherconsiderations as are well known in the art.

In one embodiment, the sol-gel composition is delivered into at least aportion of the distal end of the lumen in a solid form. In somecircumstances, it is preferable that the delivered composition protrudefrom the lumen thereby providing a mating mechanism for the distal endof the other lumen so that aligning the distal ends of the two lumen isrelatively easy.

Waxes

Other solid mass materials useful in this invention includebiocompatible waxes.

The term “wax” as used herein means a relatively low-meltingtemperature, high-molecular-weight, organic mixture or compound, similarto fats and oils but lacking glycerides. See, Dorland's MedicalDictionary (2004, W.G. Saunders, herein incorporated by reference forvarious definitions under the “wax” listing).

As noted by Dorland's, waxes may originate from natural sources (e.g.,insects or plants) or may be synthetics, and most are fatty acid estersand alcohols with some hydrocarbons. Other moieties may include lauricacid, myristic acid, palmitic acid, stearic acid, arachidic acid,lignoceric acid, palmitoleic acid, oleic acid, linoleic acid, linolenicacid, arachidonic acid and other biocompatible fatty acids that areendogenous to the treated patient as well as mixtures thereof.

The materials are not all-inclusive, and the principal useful featureherein is the ability of the wax to be “melted” or substantiallyliquefied with heat or dissolved in the body fluid once flow isreinstated, particularly in situ, at temperatures which are notinjurious to live tissue (if used pursuant to a surgical procedure on alive patient). The melting point of the waxes can be adjusted byconventional melting point depression by mixing two or more waxestogether. For example, lauric acid has a melting point of 44.2° C. andslight depression of this melting point by mixing with another suitablefatty acid can bring the melting point down to 40 to 42° C. Lowtemperature polyester waxes, such as “Steedman's wax” which have amelting temperature of about 37° C. (human body temperature) may be usedin some circumstances. See, Steedman, H. F., Nature 179:1345 (29 Jun.1957).

In one embodiment, the wax can be preformed into a “stick” configurationof predetermined diameters. The clinician can then insert a portion ofthe wax into a first lumen with the remaining portion providing a matingmechanism for the distal end of the other lumen so that aligning thedistal ends of the two lumen is relatively easy.

For microsurgical techniques involving human or other mammalian bloodvessels, the diameter of between about 0.5 and 1.5 mm is probablysuitable. For other purposes, such as intestinal anastomosis or largevenous surgeries, the diameter may be several centimeters (“cm”).(Although the term “diameter” is used, if the biocompatible stick is notcylindrical, the area of the surface of the terminus is the relevantmeasurement for determining what will fit into distal termini of tubulartissue.)

Thixotropic Agents

Still other solid mass materials useful in this invention includethixotropic or other non-Newtonian fluidic agents. These materials usedeformation, or shear stress, for phase change along the solid to fluid(or vice versa) continuum.

In general, for fluids demonstrating non-Newtonian dynamics, viscositychanges with applied stress or applied shear rate. Thixotropic, or othernon-Newtonian fluids, become more or less viscous with applied movement.For example, some thixotropic agents become less viscous subjected tostresses above a critical level. These shear-thinning fluids may beinserted into immobilized tubular tissues to stabilize the distal endsas described herein. Upon joining, movement may be applied to thenow-sealed tissues to liquefy the thixotropic agent. These stresses maybe applied externally or may arise naturally from the peristalticpressure in the circulatory system. Thixotropic agents include variousbioabsorbable or dissolvable clays, materials with corn starch or othercarbohydrate-based materials, and other colloidal and other materials asare available to those of skill in the art. It is contemplated that thethixotropic agents suitable for use in the present invention will have ayield stress of from about 100 to about 500,000 Pascals, preferably fromabout 8,000 to about 50,000 Pascals or 10,000 to about 50,000 Pascals,and even more preferably from about 12,000 to about 40,000 Pascals.

Thus, as thixotropic agents are used herein for their relatively solidform in supporting distal termini in tubular tissues, it may beinitially deployed in a less viscous state, and allowed to “rest” or notbe subject to shear-thinning movement. Upon satisfactory adjoining ofthe tissues, shear-thinning stress may be locally applied.

Additional Moieties

The solid mass compositions used in the methods of this invention mayinclude one or more additional moieties. For example, a biologicallyfunctional agent, a dye and/or a contrasting agent may be added to thesolid mass to provide additional functionalities for the solid support.

Biologically active moieties or agents may include, without limitation:

-   -   antithrombotic agents, such as coagulants (for example heparin),        platelet inhibitors, and thrombolytic agents;    -   anti-anginals, such as beta-blockers, calcium channel blockers,        and nitrates;    -   antiinfectives, such as antibiotics, antiviral and antifungal        agents;    -   analgesics and analgesic combinations;    -   antiinflammatory agents;    -   antiarrhythmics;    -   antihypertensives;    -   heart failure agents;    -   wound healing agents;    -   antiasthmatic agents;    -   antidiuretic agents;    -   antineoplastics;    -   antipyretics;    -   antispasmodics;    -   anticholinergics;    -   immunosuppressives;    -   sympathomimetics;    -   central nervous system stimulants;    -   parasympatholytics;    -   hormones such as growth hormones, estradiol and other steroids,        including corticosteroids;    -   muscle relaxants;    -   lipid lowering agents;    -   anti-ulcer H2 receptor antagonists, anti-ulcer drugs;    -   anorexics;    -   antiarthritics;    -   sedatives;    -   tranquilizers;    -   anti-restenosis agents;    -   anti-proliferatives, such as everolimus, sirolimus, paclitaxel,        and biolimus (Biosensors International, Singapore);    -   pro-angiogenic agents;    -   proteins—for example, growth factors, gene vectors containing        growth factors, such as fibroblast growth factor (FGF),        insulin-like growth factor (IGF), vascular endothelial growth        factor (VEGF), B-cell growth factor (bGF), hepatocyte growth        factor (HGF), monocyte chemotactic protein-1 (MCP1), and those        described in U.S. Pat. No. 6,702,744 (Mandrusov et al), which is        incorportated by reference in its entirety. The proteins may be        in protein or gene form, or combinations thereof; and    -   gene-therapies.

Examples of the above biologically active agents and other agentssuitable for use in the solid mass are described in, for example, U.S.Pat. No. 6,702,744 (Mandrusov et al), U.S. Pat. No. 7,169,404 (Hossainyet al), U.S. Pat. No. 6,908,624 (Hossainy et al), U.S. Pat. No.6,899,729 (Cox et al), U.S. Pat. No. 7,169,178 (Santos, et al), all ofwhich are incorportated by reference in their entirety.

The biologically active moiety may be optionally formulated in sustainedrelease or in gene vectors.

The biologically active moiety may optionally be therapeuticallyeffective as administered, and the subject solid mass may optionallycontain a therapeutically effective amount of the biologically activemoiety.

A therapeutically active moiety will be a biologically active moiety. Atherapeutic effect is one which seeks to treat the source or symptom ofa disease or physical disorder. The term “treat” or “treatment” as usedherein refers to: (i) preventing a disease or disorder from occurring ina subject which may be predisposed to the disease or condition but hasnot yet been diagnosed as having it; (ii) inhibiting the disease ordisorder, i.e., arresting its development; and/or (iii) ameliorating orrelieving the disease or disorder, i.e., causing regression of thedisease. A therapeutically effective amount is sufficient to establishcausation of a therapeutic effect, as determined by relevant clinicalstandards. The therapeutically effective amount will vary depending uponthe specific agent incorporated, the subject and disease condition beingtreated, the weight and age of the subject, the severity of the diseasecondition, the dosing regimen to be followed, timing of administration,the manner of administration and the like, all of which can bedetermined readily by one of ordinary skill in the art.

Biologically active moieties may also be incorporated into the ligation(joining) composition applied to the tubular tube tissue so adjoinedincident to the anastomosis. As described herein, ligation can beaccomplished any number of ways, and, if the present anastomosismaterials are used, sutures or an adhesive may be most practicable.

Contrast agents, such as a biocompatible radio opaque material capableof being monitored by, for example, radiography, may also be added tothe solid mass to track and monitor the solid mass and/or the procedure.The contrast agent may be water soluble or water insoluble andpreferably does not contain radioactivity above the native or endogenousamounts naturally occurring in the elements employed.

Examples of water soluble contrast agents include metrizamide,iopamidol, iothalamate sodium, iodomide sodium, and meglumine. Examplesof water insoluble contrast agents include tantalum, tantalum oxide, andbarium sulfate, each of which is commercially available in the properform for in vivo use including a preferred particle size of about 10microns or less. Other water insoluble contrast agents include gold,tungsten, and platinum powders.

The solid mass compositions may also include a suitable biocompatibledye for visualization, especially when a lumen has a thick wall. Suchdyes are well know in the art.

III. Anastomosis Methods

It is contemplated that the present invention can be applied to anyanastomotic procedure that connects one hollow tissue structure (lumen)to another hollow tissue structure (lumen), such that the spaces withineach hollow tissue structure are connected thereby forming a conduit (anintraluminal conduit). It can be used in a microvascular context, whichis performed between ends of blood vessels in the course of, forexample, reattaching severed body parts and/or transplanting organs ortissue. It can also be used in minimally invasive procedures orpercutanteous approaches with catheters. It can be used to connectnon-conjoined lumens arising from surgical procedures wherein theoriginally intact lumen has been severed for the purposes of, e.g.,removing a blockage or partial blockage. Suitable lumens include, by wayof example, the vasculature, the vas deferens, the fallopian tubes, theurinary tract, tear ducts, bowel, mammary glands, alimentary ducts,pancreatic ducts, bile ducts, etc. (Specific anatomical lumens may bereferenced by their conventional anatomical nomenclature such as tubes,ducts or vessels, as used in context herein.)

In one embodiment used for illustrative purposes only, the anastomosisis performed during coronary artery bypass graft (CABG) procedures orperipheral bypass procedures to connect two blood vessels or one bloodvessel with one synthetic graft. The blood vessels connected togethermay have different diameters. Further one or both of the vessels may bevery small, and may be on the order of about 1 to 5 millimeters (“mm”).The microvascular anastomosis procedure using the present invention maybe performed under a microscope.

Referring now to the Figures, the invention is described schematicallyand in a simplistic fashion in order to convey the general concepts.With these concepts in mind those skilled in the art will contemplatedetailed specific embodiments of the invention which are intended to beencompassed by the present claims. FIG. 1 shows a schematiccross-sectional view of a lumen which may be a vessel 1 which has flow 2running there through. A portion of the vessel indicated by points 3 and4 has a restricted flow due to the formation of blockages 5 and 6. Theblockage may become so severe that the flow is completely blocked. Thoseskilled in the art will appreciate that a range of different treatmentsare available for restoring flow.

Prior to the operation to restore flow, the vessel needs to be occludedto stop the fluid (e.g., blood) flow. Such occlusion is important foranastomosis involving a blood vessel to prevent excessive loss of bloodand complications caused by a continuous blood flow. However, clampingmay not be necessary for anastomosis of other types of lumens wherethere is no continuous flow of fluid or the amount of fluid does notcomplicate the procedure.

Thus, as shown in FIG. 2, clamps 7 and 8 have been placed on the vesselsto stop the blood flow in the section between the clamps prior toremoval of the blocked section. Such clamps can be any surgical clampssuitable for clamping the vessels to be operated on from the outside,such as clamps, clips and tourniquets or snares. After clamping, aportion of the vessel 1 which has the restricted flow between the points3 and 4 is then surgically removed. Those skilled in the art willunderstand that the distance between the points 3 and 4 is sufficientlysmall such that the ends can be brought into contact with each other torestore flow.

Referring now to FIG. 3, the inside of the vessel 1 between the clamp 7and the end 3 has been filled with the phase-reversible sol-gel 10 whichis shown in solid phase by the crossed markings. The area between theclamp 8 and the end 4 is being filled with sol-gel 11 in a liquid phase.In an optional embodiment, the thermoreversible sol-gel 10 can beintroduced in its gel phase so as to ease delivery into the vessel. Thesol-gel is injected from a suitable source such as a hypodermic needle9. When the sol-gel material is in the hypodermic needle it may beeither in a flowable liquid phase or in a gel phase. In the former case,the composition will undergo a phase transition to a solid gel phase(10) upon the application of the suitable environmental stimuli such asheat. In the latter case, the composition is delivered in a solid gelphase (10) and maintained in that phase by continuing the application ofthe suitable environmental stimuli such as heat. It is contemplated thatthe later is more convenient when the sol-gel composition has a lowertransition temperature, for example, a transition temperature of lessthan 30° C.

It is contemplated that additional amount of the sol-gel composition maybe applied to the lumens during the joining step if needed.

Alternatively, the procedure can be formed by partially suturing the twolumens, for example, applying a few sutures on the opposite sides of thelumens to bring the lumens in a connecting position. Thethermoreversible sol-gel composition can then be applied to thepartially sutured opening and form a continuous gel column to fill thelumens to give the structural support for the subsequent procedure thatcompletely joins the lumens. The amount of the sutures applied for thispurpose is not intended to fully join the lumens but is to keep thelumens together so that the gel can be applied to both lumens together,for example, in some embodiment, the sutures are 4-6, or 2-4 andpreferably 1-2 sutures on each side.

The sol-gel material is included in a sufficient amount so as tomaintain at least a portion of the distal end of vessel 1 open. In theabsence of some force, the side walls of the vessel 1 will contact eachother and cause the vessel to close in the absence of flow through thevessel. The solid gel phase (10) imparts sufficient structural rigidityto the lumen to permit the anastomosis to proceed with the vessel in itsfully filled form.

As shown in FIG. 4, the two lumens can be joined by applying an adhesiveor glue 12 on the two ends of the lumens as well as on the outer surfaceof the vessel at points 3 and 4 and sealed together. Although FIG. 4shows the use of a glue, it is to be understood that as describedherein, joining or ligation can be accomplished any number of ways, and,if the present anastomosis materials are used, sutures or an adhesivemay be most practicable. Sutures are well known in the art as aresurgical glues or adhesives. Such glues are biocompatible and aregenerally cyanoacrylate-based adhesives, fibrin-based adhesives,polyurethane-based adhesives, polyisocyanate-based adhesives, and UVcurable glues. The suture or glue may contain biologically activemoieties such as antimicrobial agents (e.g., U.S. Pat. No. 5,762,919).

Due to the presence of the gel (in solid phase) significant amounts ofadhesive can be used without resulting in vessel closure. In the absenceof a structural support, such as the phase-reversible sol-gel 10 in thisexample, being present within the vessel the application of pressure tothe outside of the vessel such as by the application of glue can causecollapse of the vessel. However, since the phase-reversible sol-gel 10is holding the vessel open, glue can be applied liberally not only tothe ends 3 and 4 which are to be sealed together but the glue 12 can beapplied along the surface of the vessel 1 near the point where the sealis to take place. Thus, as shown in FIG. 4, glue has been applied on theoutside of the vessel 1 on either side of the point where the ends aresealed. The glue can extend outward in any desired amount. However, withsmaller vessels extending the glue out a distance of about 1 mm to about10 mm is generally sufficient. The glue can extend outward around theentire circumference of the connecting point. After the adhesive 12 hasbeen allowed to cure and seal bonds between the two ends of the vessel,the clamps 7 and 8 can be removed. In one embodiment the glue alsopenetrates inward to the surface of the gel thereby providing adherenceof the entire tissue cross-section of the first lumen to the secondlumen. In another embodiment, the glue is applied not only to the outersurface but also to the cross-sectional surfaces of the lumens to beclosed. In a still further embodiment, a solid mass, such as a sol-gel,has a superior wetting characteristic to the vessel when compared to theglue, to inhibit the glue from penetrating into the inner surface oflumen.

The lumens may also be joined by using laser, such as laser welding orlaser soldering. See, e.g., D. Simhon, in Lasers in Surgery: AdvancedCharacterization, Therapeutics, and Systems XIV, Vol. 5312, 176-185(2004); S. Nakata, et al, The Journal of Thoracic and CardiovascularSurgery, 98, 57-62, 1989; and Sanford L. Klein, et al, Microsurgery,15:4, 287-288, 2005. However, laser anastomoses have been reported tocause side effects such as soldering the lumen shut, hemorrhage anddegeneration of collagen and protein in the adventitia and media, andunder conventional laser anastomosis conditions. See, e.g., S. Nakata,et al, The Journal of Thoracic and Cardiovascular Surgery, 98, 57-62,1989; T. Bavbek, et al, Opthalmologica 219, 267-271, 2005. It iscontemplated that placing a solid mass, such as a sol-gel composition,inside the lumens will help to keep the end of the lumen open andprotect the tissue from being damaged by laser.

Turn to FIG. 5, when the clamps 7 and 8 are removed, the stimuli such asheat which was being applied to maintain the gel in a solid state isremoved and gel changes phase to a liquid. Once the gel reverses itsphase change to become a liquid and the blood flow against theliquefying gel causes the gel to be dispersed, the vessel reopens asshown in FIG. 6.

In the case where the sol-gel composition has a transition temperatureat or below the body temperature, such as from about 0° C. to about 35°C., the transition of the sol-gel composition from the solid state tothe liquid state can be induced by cooling the connected vessel by, forexample applying cold water, a cold saline solution or ice.

In the case where the sol-gel transition stimulus is ionic strength, thephase change may be induced by allowing the blood, which may have adifferent ionic strength than the gel, to flow to the gel and induce thephase transition from a gel to a liquid.

In the case where waxes are employed, heat can be applied to the joinedlumens to melt the wax. Moreover, if the clamps are removed prior toapplication of heat, both melting and dissolution of the wax into thebody fluid can occur.

In the case where thixotropic agents are employed, the application ofshear stress to the mass, such as gentle squeezing of the joined lumensor the stress arising from the pumping action of the heart, willsignificantly reduce the viscosity of the mass and render it flowablewith the body fluid.

At this point as shown in FIG. 5, the glue 12 has cured or hardened. Theglue 12 seals the ends of the vessels together but also is applied tothe outer surface of the vessel on either side of the point ofconnection where it is circumferentially applied. Accordingly, when theglue 12 hardens the glue 12 acts as an external stent holding the vessel1 open after the gel has liquefied. Although it is not necessary to havethe glue forming the external stent, this can provide an additionaladvantage. The glue may be designed so that it remains in place for aconsiderable period of time or designed so that it dissolves slowly overtime as the two ends of the vessel grow together.

Those skilled in the art will understand that particularly hightemperatures will not be useful for treating a patient as this may causeundue heat damage to live tissues. It is contemplated that sol-gelcompositions with a transition temperature of between 0° C. to 45° C.can be used in the methods of this invention. In particular, atransition temperature of around 42° C. to maintain the gel in the solidstate might be used provided the gel will revert to its liquid state ataround body temperature or 37° C. It is contemplated that a sol-gelhaving a transition temperature that is lower than the body temperature,such as from 0° C. to 35° C., or from 15° C. to 35° C., can also beused. In such a case, the gel can be converted to its liquid state bylowering the temperature of the anastomosis site to below the transitiontemperature by cooling, for example, with ice or cold saline orphosphate buffered saline.

In this particularly described embodiment, temperature is used as themechanism for causing the gel to undergo a phase change. However, asindicated above, other factors such as pH, ion concentration such ascalcium ion concentration, concentration of the composition, pressure,electric field, magnetic field, electron magnetic radiation, light orultraviolet light, osmolarity, ultrasound, and the like and combinationsthereof can be used. For example, some sol-gel compositions are at a gelstate in solution with a high ionic strength but undergo a phasetransition to the liquid state when the ionic strength is reduced. Thus,it is contemplated that a gel composition having a high ionic strength,e.g. a hypotonic composition, can be injected to the lumens to be joinedand upon joining the lumens, the ionic strength can be reduced when theclamps are removed and blood flow enters into the area of the ligation,causing the gel composition to liquefy.

Additionally, the gel may be removed by dissolving in the body fluid orby a combination of dissolution and a phase transition. For example, thegel may dissolve in blood once the clamps are removed and blood flowenters into the area of the ligation.

Regardless of the particular parameter used to undergo the phasetransition, the formulation will take into consideration factors such asthe normal temperature, normal pH, normal ion concentration of thesubject being operated on. In one embodiment, the gel will be in aliquid phase when the parameter such as temperature, pH or calcium ionconcentration is at or very close to that of the surrounding environmentand will be in a solid or gel phase when it is raised somewhat above orbelow the normal point but not sufficiently far from normal so as to bedamaging to the tissue. Thus, high temperatures, extremely high or lowpHs, as well as very high or low ion concentrations, would not be used,as such would likely cause damage to the surrounding tissue. Whenelectric field is used as the trigger, the electric voltage and currentneeded to effect a phase transition should be minimal, specially incases where the cells and tissues may be very sensitive to a change inelectric field, such as in a cardiovascular surgery.

It has been demonstrated in mammalian experiments, that by performing ananastomosis procedure using the method and composition of the presentinvention, the time required to connect the blood vessels issignificantly reduced to an average of 3 minutes 11 seconds (rangingfrom 55 seconds to 6 minutes), from an average of 29 minutes 15 seconds(ranging from 20 to 49 minutes) with conventional hand-sewn anastomosisprocedures. See Example 1. This in turn resulted in improved outcomes ofthe procedures in terms of the diameters and patency rates of thevessels connected, complications caused by the procedures and themortality rates of the subjects treated. See Example 1. Further, theexperiments showed that anastomotic flow and burst strength at six weeksafter the anastomosis procedures using the present invention were aboutthe same if not better than using conventional hand-sewn procedures.

The methods of this invention can be applied to end-to-end, end-to-side,and side-to-side anastomosis. It can be used to join two or more bloodvessels in a patient, or join a blood vessel of the a patient with alumen selected from the group consisting of arteriovenous graft,arteriovenous shunt, allograft, xenograft, synthetic graft, and cadaverxenograft.

It is contemplated that the methods of the present invention are usefulin other medical procedures, such as reversal of vasectomy, reversal offallopian tube ligation, and reconstructive tubal surgeries to treatblocked or damaged fallopian tubes. The method can also be used toconnect an AV graft or AV shunt or fistula to a blood vessel forhemodialysis as well as for bypass strategies for below the knee bypass,such as in the treatment of a peripheral arterial disease. Further themethod of the present invention can be used in alimentary anastomosis.Significant leak rates (about 2-5%) have been resulted by currentalimentary anastomosis procedures. Many of the leak incidents are fatalor lead to significant morbidity. Because the alimentary tubes beingligated can be supported inside by the sol-gel of the present inventionand the glue can be applied circumferentially outside the point ofconnection, thus allowing complete sealing, it is contemplated thatanastomosis using the method of the present invention will significantlyreduce the leak rate and lead to decreased mortality and morbiditycaused by alimentary anastomosis. The methods and compositions of thepresent invention can also be used in the treatment of conditionsinvolving urinary tracts, tear ducts, bowel, mammary ducts, pancreaticducts, bile ducts, and the like.

IV. Kits of the Invention

One aspect of this invention is in the form of a kit of parts. The kitmay include specific instructions with respect to how to carry out themethodology of the invention as exemplified above.

Further, the kit may include a container containing the solid mass orsolid mass precursor e.g., the solution phase of a sol-gel composition,preferably in sterile form, and a delivery device. The delivery devicemay be a syringe, a pipette or tweezers, catheter or laparoscopic tool,and the like. Alternatively, the kit may contain a delivery deviceloaded with a flowable form of the solid mass material of the typedescribed above, again preferably in sterile form. For example, the kitmay contain a syringe already loaded with a sterile sol-gel compositionor an ampule made from glass or plastic that contains a sterile sol-gelcomposition, and which has a tip that may be cut open to apply thesol-gel contained therein.

When a solid mass material is provided in the kit, it can be in a rodform of defined diameter so as to match the diameter of the lumen towhich the solid mass is to be inserted.

Still further, the kit may include one, two or more clamps of the typewhich might generally be used in connection with the lumen or type ofvessel (or duct, tube, etc.) being treated. Still further, the kit mayinclude sutures or surgical glue of the type described above. Stillfurther, the kit may include a triggering component or element which,when activated, results in phase transition of the sol-gel material. Forexample, the triggering component may be a component which whenactivated generates heat, cold or other triggering conditions, which canbe used to induce the gel-formation and/or maintain the sol-gel in itssolid or gel like phase until it is to be removed or it may trigger agel to liquid transition. Such triggering elements may include, but arenot limited to, a heat source, such as a heated air blower capable ofdelivering warm air, and heating pads, an infrared heating apparatus,etc, that can maintain a temperature sufficient to induce the change ofphase of the thermoreversible sol-gel; a cooling source; a light energysource; an electric source; an ultrasound source; an irrigated liquidstream source; or sources to generate other triggers described herein.Further, the delivery device may be coupled with a triggering element,such as a heating or cooling component, and serves as both a deliverydevice and a triggering element. The kit may further include a adhesivedelivery system.

The kit may further include one or more pharmaceutically active drugswhich may be separate from or incorporated into the solid mass or itsliquid precursor. Thus, for example, the drug which may be providedseparately in the kit or incorporated into the solid mass or its liquidprecursor may include an anticoagulant such as heparin. The solid massor its liquid precursor may further include an antibiotic or othermaterial such as a wound healing medicament which aids in healing of thevessel.

Commercially, for ease in practical application, materials may beprepared so that they are sterile and substantially pyrogen free, forexample, in accordance with regulatory requirements. Materials anddevices may be prepackaged in sterile packaging.

V. Examples

Examples 1-3 and 8 are working examples demonstrating the practicabilityof the present invention. Example 1 demonstrates that, for athermoreversible composition, gelation temperature may be optimized bythe addition of an additional moiety. Example 2 demonstrates thepracticability of the present invention in an anastomosis animal model,demonstrating improved results over traditional methods in terms ofincreased body fluid flow and decreased mortality, in preliminaryresults. Example 3 demonstrates the additional aspect of use of thepresent methods and compositions for sustained delivery of abiologically active molecule, here, heparin, the blood thinner. Examples4-7 are prophetic examples of practicability in human anastomosisprocedures.

Example 1 Changing the Sol-Gel Transition Temperature of aThermoreversible Sol-Gel Composition with the Addition of a Protein

One embodiment of the present invention relates to exploitation of thesol-gel transition temperature of thermoreversible sol-gel compositions,and this working example demonstrates how the gelation temperature maybe altered to be slightly above the normal body temperature. Therefore,this example allows a sol-gel material to assume a gel state inside thedistal portion of the lumen when the temperature is temporally raised toabove the transition temperature so that the geometry of the distalportion of the lumen is stabilized during the anastomosis procedure.After the anastomosis procedure, the temperature is returned to normalbody temperature, which is below the transition temperature of thesol-gel material, so that the sol-gel material liquefies and becomesflowable in the conjoined lumen. This working example demonstrates thatwith an appropriate concentration of a protein, here bovine serumalbumin, the gel-transition temperature of a thermoreversible sol-gelcan be modulated to be slightly above the normal body temperature.

A thermoreversible sol-gel which can be used in connection with thepresent invention is known as poloxamer, also known under the tradenamePluronic® and Lutrol®. Examples of poloxamers include poloxamers 407,338, 188, and 118. The various pharmaceutical and pharmacologicalcharacteristics of poloxamer 407 are described within Dumortier,Pharmaceutical Research, Vol. 23, No. 12, December 2006. poloxamer 407is a water soluble block copolymer comprised of poly(ethylene oxide) andpoly(propylene oxide). The block polymer component is brought intosolution in water. A graph of the modulus of the poloxamer 407 in water(no BSA) over time is shown in FIG. 7 by the line graph with therectangular data points. FIG. 7 shows that poloxamer 407 undergoes aphase transition between about 25° C. and about 30° C. where the modulusor stiffness of the polymer substantially increases forming the gel. Itis contemplated that such a sol-gel composition may be used in themethod of the invention, where the sol-gel composition solidifies uponinjection into the lumen having a temperature close to the bodytemperature, for example, 35° C. to 37° C. After the lumens are joined,the gel can be removed by allowing the body fluid to enter the site ofligation and dissolve the gel or by cooling the temperature of thejoined lumens to below the transition temperature with, for example,cold saline solution or ice.

In a preferred embodiment of the present invention, the sol-gelcomposition, such as a poloxamer 407 solution, is modified so as toshift the point at which the composition undergoes a phase change to ahigher temperature. Although this can be accomplished by changing theconcentration of the polymer in water, if this route is taken it tendsto decrease the resulting modulus of the polymer gel formed.

Decreasing the modulus, or elastic modulus (G′), is not desirable foruse in connection with the present invention. The compositions usefulfor this invention should have modulus that is sufficiently high towithstand the pressure applied on the outside of the vessels and to keepthe vessels open when the vessels are manipulated during the anastomosisprocedure. It is contemplated that the gels of the present inventionshall have elastic modulus (G′) values of from about 100 to about500,000 Pascals, and preferably from about 10,000 to about 50,000Pascals, and more preferably from about 12,000 to about 40,000 Pascals.

Accordingly, it has been contemplated that by the inclusion of anothermolecule it might be possible to shift the phase transition point interms of increasing the temperature at which the phase change takesplace without decreasing the resulting modulus of the gel formed. It hasbeen found here that by including a transition condition modulatingagent which is biocompatible, such as a protein, it is possible to shiftthe temperature point at which the composition undergoes a phase change.

The data shown in FIG. 7 indicate that Bovine Serum Albumin (BSA) hasbeen added first in a concentration of about 0.5% and then aconcentration of about 1.0% and then a concentration of about 5%. Theresults shown in FIG. 7 indicate that by including the BSA in acomposition in an amount of about 1% the phase transition point isshifted so that it occurs at about body temperature or at about 37.5° C.

The resulting composition with about 1% BSA provides a phase transitionmaterial which is biocompatible and provides a desirable transitiontemperature which has been varied without significantly changing themodulus of the resulting gel as compared to the gel without the addedBSA.

A preferred formulation is comprised of about 17% polymer such aspoloxamer 407, about 1% biocompatible compound such as BSA and about 82%water or a salt solution such as phosphate buffered saline solution.Those skilled in the art will understand that each of these componentscan be varied in an amount of about ±50%, about ±25%, about ±10%, about±1% and, depending on the particular polymers and biocompatiblecompounds used, desirable results may be obtained.

In some embodiments, the biocompatible polymer may have a molecularweight in the range of about 8,000 to 16,000, more preferably 10,000 to16,000, or more preferably 10,000 to 14,000 and most preferably about12,600. (As indicated above, the term “about” as used in this contextreflects that commercial preparations of the monomers or polymers asdescribed herein may contain mixtures of varying molecular weightsincident to the commercial manufacturing process.) That polymer iscombined with a biocompatible compound which may be a protein andpreferably a protein which does not elicit an immune response. Theprotein may be a blood protein such as an albumin and specifically maybe Bovine Serum Albumin or Human Serum Albumin. (Also as indicatedabove, recombinant versions of such proteins (or any proteins asdescribed herein) may be preferred for commercial manufacturing reasons,for assurance of no animal-originating pathogenic agents).

In one embodiment, the polymer is present in the composition in anamount of about 15% to 20% by weight, or 16% to 18% by weight or 17% byweight. The polymer is combined with the biocompatible molecule in anamount of about 0.5% to 2% by weight or about 1% by weight. Theremainder of the composition is water or phosphate buffered saline. Theresulting composition is further characterized by undergoing a phasetransition at a temperature higher than the phase transition temperaturewhen the biocompatible compound is not present with a change in modulusof 25% or less, or 10% or less, or 5% or less. More particularly theresulting composition undergoes a phase transition in a relativelynarrow range of about 35° C. to about 40° C. or about 36° C. to about39° C. or more preferably about 37.5° C.

Those skilled in the art will be able to contemplate other phasetransition materials which could be used in connection with theinvention upon reading this disclosure and examining the data provided.The phase transition may be brought about by a change in condition otherthan temperature such as a change in pH and those skilled in the artwill understand that that pH change may be a change which is broughtabout at a pH very close to the pH of human blood or a pH of about 7.2.

Presented here is a protocol for a 17% poloxamer 407 with 1% BSA. One ofskill in the art may use different concentrations of thethermoreversable material or the protein.

The following materials were mixed together to form 100 ml (100 g)solution of 17% poloxamer 407 with 1% BSA:

-   -   Phosphate buffered saline (“PBS”): 92 g, Gibco #10010, pH 7.4,        with Ca²⁺ and Mg²⁺;    -   Bovine Serum Albumin (“BSA”): 1 g, Sigma A2153-50 g;    -   poloxamer 407: 17 g poloxamer 407, BASF Pluronic® F 127 NF Prill        poloxamer 407, Material 30085239;

Solutions having 17% poloxamer 407 and 0.1% BSA to 5% BSA were preparedaccordingly.

To determine the sol-gel transition temperature (the temperature atwhich the poloxamer 407 transitions from liquid to gel amounts of eachsolution were placed between the parallel plates of a stress rheometer(a TA Instruments G2 rheometer was used). The plates were 4 cm indiameter and the gap was set to 1 mm. The elastic modulus was measuredusing the rheometer at a frequency of 1 Hz and a strain of 0.1 atdifferent temperatures. FIG. 7 is a graph depicting the modulus as afunction of temperature. For BSA concentrations at or below 1%, thegelation temperature increased. The gel transition temperature, markedlydecreased as the BSA concentration grew from 1% to 5%.

Example 2 Efficacy and Safety in an Animal Model Using ThermoreversibleAnastomosis Compositions

This working example demonstrates that the present anastomosiscompositions are efficacious in joining tubular tissues to result inbodily fluid flow through the resultant continuous lumen.

Anastomosis Using Thermoreversible Gel

Anastomosis were performed in normal rats. The Poloxamer solution inthis example refers to the thermoreversible composition containing 17%poloxamer 407 and 1% BSA, as prepared in Example 1, above. All animalsare treated and cared for in accordance with all applicable laws andregulations, and in accordance with good laboratory practices.

End to End Anastomosis Surgical Method Performed on Cardiac TubularTissues in Rats:

Rats were anesthetized with isoflurane and prepped in sterile fashionwith 70% ethanol. The aorta was exposed and isolated with blunt andsharp dissection through a midline laparotomy incision. The aorta wasclamped proximally and distally, and subsequently divided and flushedwith heparinized saline. In some cases the rat and the poloxamersolution were warmed to 40° C. with sterile water, and then thepoloxamer solution was injected in a semi-solid state and in other casesthe poloxamer solution was injected into the vessels as a liquid andthen heated to 40° C. with a convection source to solidify it. Afterdirect reapproximation by pushing the ends of the aorta together, thecyanoacrylate adhesive was applied and allowed to cure for 60-120seconds. The clamps were then removed, and the midline incision wasclosed in layers with 5-0 vicryl (Ethicon, Inc., Somerset, N.J.) and 4-0nylon (Ethicon) in a running fashion.

End to Side Anastomosis Surgical Method:

Rats were anesthesized, shaved, and prepped in standard sterile fashion.A midline laparotomy incision was made and the abdominal organseviscerated into a moist 4×4 gauze. The iliac bifurcation was isolatedwith blunt dissection, and the abdominal aorta was clamped proximallyand the iliacs were clamped distally. The left iliac was divided justdistal to the bifurcation and an arteriotomy was made in the rightiliac. The vessels were then flushed with heparinized saline. Theabdomen was warmed at the same time the poloxamer solution was warmed toa gel (about 40° C.) which was then injected. The left iliac wasapproximated to the right iliac using the sliding clamps (one clamp wason the proximal aorta and the other was on the distal left iliac). Oncethe ends were opposed without tension, the cyanoacrylate was applied andallowed to set (˜5 min). Clamps were then removed and blood flow isrestored.

Conventional Handsewn Anastomosis:

Rats were anesthesized, shaved, and prepped in standard sterile fashion.A midline laparotomy incision was made and abdominal organs wereeviscerated. The aorta was isolated with blunt dissection and clampedproximally and distally and then divided. The two vessel ends wereflushed with heparinized saline. The anastomosis was performed with arunning 10-0 nylon suture. Each suture was full thickness through alllayers of the aorta. Any areas of leakage were controlled with a simpleinterrupted suture, and the clamps were removed. For the end-to-sideanastomosis, the iliac bifurcation was isolated as previously describedand clamped proximally and distally. The left iliac artery was dividednear its origin and reapproximated to the right iliac artery using theclamps. An arteriotomy was made in the right iliac artery and both endsware flushed with heparinized saline. The anastomosis was then performedwith a running 10-0 nylon suture using standard microsurgical techniquesand all areas of leakage were controlled with a simple interruptedsuture. No successful end-to-side anastomosis were completed with thehand sewn technique.

Results

To evaluate the effectiveness of anastomosis using thermoreversible gel,the patency, flow and burst strength of the vessels connected weremeasured. The diameters of the anastomotic vessels were measured usingconventional CT angiography. Patency and flow were determined throughultrasonic Doppler imaging using a visual sonic machine.

Burst Strength were Determined According to the Following Procedure:

Rats were anesthesized and native rat aortas were harvested prior to theoperation and operated rat aortas at designated time pointspostoperatively through a midline laparotomy incision. The aorta wasclamped proximally just below the renal arteries and just above theiliac bifurcation. Any small branches were identified and ligated. Theharvested aorta was then flushed with saline to remove blood andidentify any non-ligated branches. The aorta was then attached to a 22gauge angiocath using 5-0 silk suture at both ends. The angiocath wasequipped with an adapter than attaches directly to the burst strengthdevice. Saline was flushed through the machine and through the aorta atcalibrated pressures which were increased incrementally until theanastomosis burst.

Table 1 shows the anastomotic diameters, anastomotic flow, and burststrength of end-to-end anastomotic vessels connected using thethermoreversible sol-gel composition or by handsewing at six weekspost-operation. Patency and survival rate of end-to-end or end-to-sideanastomosis using the two methods are compared in Tables 2 and 3.

TABLE 1 End-to-End Anastomosis results* Anastomotic Anastomotic Time peranastomosis Diameter Flow Burst Strength TRGA Average: 3 min. 11 sec.1.93 mm 75 ml/min 1345 mmHg group** Range: 55 sec. to 6 min. (SD +/− .23mm) (SD +/− 34 ml) (SD +/− 190 mm) handsewn Average: 29 min. 15 sec.1.23 mm 63 ml/min 1248 mmHg group Range: 20 to 49 min. (SD +/− .43 mm)(SD +/− 29 ml) (SD +/− 206 mm) p-value 0.027 not significant notsignificant *preliminary results at six weeks **Thermoreversible gelanastomosis group

TABLE 2 End-to-End Anastomosis results* Procedure Number Patency Rateused of rats among survivors Number and causes of deaths TRGA n = 26100% One early anesthetic death. Hand-sewn n = 25  86% Three earlydeaths from perioperative leak and hemorrhage; Two late deaths; Twodistal ischemic events requiring sacrifice.

TABLE 3 Side-to-End Anastomosis results* Procedure Number Patency Rateused of rats among survivors Number and causes of deaths TRGA n = 13100% No deaths or ischemic events. Hand-sewn n = 10  10% 60% withsignificant limb ischemia requiring sacrifice; One patent anastomosisoccluded ipsilateral iliac at “toe”.

Example 3 Use of Reversible Gel-Sol Anastomosis Compositions forSustained Delivery of a Biologically Functional Molecule

The present materials were used for delivery of heparin, as determinedby an enzyme linked immunoadsorbent assay. The present thermoreversiblesol-gel composition containing heparin was compared to media alone.Human umbilical vein endothelial cells were incubation for 5 minutes intrans-well plates. Heparin in varied concentrations (10, 100 and 1000U/mL) were added to the cells directly or with poloximer. Tissue FactorPathway Inhibitor (TFPI), tissue factor (TF), thrombomodulin (TM) weremeasured at 2 hr, 6 hr and 24 hr post heprin addition using a ELISA kit(R&D Systems, Minnesota USA). As shown in FIG. 8, poloxamer-mediateddelivery of heparin is more effective than direct administration ofheparin. Further, the effects of heparin persist up to 24 hours withpoloxamer mediated delivery, longer than with direct administration.This demonstrates that as the composition transitions from gel toliquid, the heparin is released for a sustained release effect.

The following Examples 4-7 are prophetic and have not yet beenconducted. Rather these examples define methods which are readilycorrelated from Examples 1-3 and 8 which were actually performed.

Example 4 Prophetic Example of Use of Wax Compositions in an AnastomosisProcedure

This prophetic example illustrates the use of a wax composition as thesolid mass to provide structural support for a lumen during anastomosis.It is contemplated that the treated mammal will be anesthetized withisoflurane and prepped in sterile fashion with 70% ethanol. The aorta isexposed and clamped proximally and distally, and subsequently dividedand flushed with heparinized saline. After being cut and flushed withsaline, the temperature of the divided aorta becomes slightly lower thanthat of the body temperature. A wax composition having a melting pointat about the normal rat body temperature, for example, a mixture ofcapric acid and lauric acid, is placed in the two open ends of thedivided aorta in a matter to maintain the structural integrity of theaorta. After direct reapproximation by pushing the ends of the aortatogether, the cyanoacrylate adhesive is applied and allowed to cure for60-120 seconds. The clamps are then removed to allow blood to flow tothe anastomosis point, causing the temperature to rise to about bodytemperature, which is sufficient to melt the wax composition andestablish blood flow through the entire aorta.

In another example, a wax composition having a melting point slightlyhigher than the body temperature is preformed into a “stick”configuration of a diameter similar to that of the above aorta. Thestick is inserted to one end of the aorta in a manner that a portion ofthe stick protrudes outside the aorta. The protruding portion of thestick is then inserted into the other end of the aorta so that the twoends are brought together. The cyanoacrylate adhesive is applied andallowed to cure for 60-120 seconds. The anastomosis point is warmed upto the melting point of the wax to melt the wax stick inside the aorta.The clamps are then removed to allow blood flow to be restored.

Example 5 Prophetic Example of Use of Thermoreversible Sol-GelCompositions for a Vavovasectomy

This prophetic example illustrates how the present invention could beused to connect tubular tissues which do not need immediate restorationof body fluid flow, but rather may benefit from a gradual healing, andtherefore, a slower degradation of the subject sol-gel material in situ.A patient desires a vavovasectomy to reverse a vasectomy. Thepractitioner locates the previously cut vas deferens termini, andre-cuts a portion to open the tubular tissue lumen. A sol-gelcomposition of pasty texture is placed into the termini of each portionof the vas deferens, thereby stabilizing the tubular geometry. Thestabilized termini are matched up, and methacrylate or other bioadhesive is applied and allowed to cure, if appropriate. The sol-gelcomposition does not immediately liquefy, but gradually biodegrades intoconstituent moieties which are absorbed by the surrounding tissue. Thesol-gel optionally locally delivers in a sustained release fashion woundhealing or anti-inflammatory biologically functional moieties, so thatthe now-reattached vas deferens does not occlude or become re-blockeddue to scar tissue or undue inflammatory response.

The procedure described above may be used in other surgical proceduresto remove blockage of other tubular tissues. It is contemplated that adye may be incorporated into the wax composition for easy alignment ofthe non-conjoined lumens, especially for a lumen having a thick wallwhere the lumen is difficult to see.

Example 6 Prophetic Example of Use of Sol-Gel Material and AdhesiveLigation

This prophetic example illustrates an example of initiation ofanastomosis using a photoinitiation solidification and anenzymatically-initiated liquefication using a sol-gel compositionengineered to have photoactivatable cross-linking initiation sites, andenzyme-recognitions site for biodegradation. The sol-gel transitionstoward solid upon exposure to the appropriate wavelength of light, andtransitions toward liquid upon exposure to the enzyme, (or becomes moreliquid) and dissolves into the systemic circulation, for example. Apractitioner deploys the substantially liquid sol-gel to the terminus ofa first tubular tissue, and applies a suitable wavelength of light forsubstantially solidifying the sol-gel. If the tubular tissue is in vivo,the light may be applied using fiber optic means, or if the tubulartissue is ex vivo, a suitable light source may be applied. The polymericbackbone of the sol-gel may be engineered to include an enzymerecognition site, such as a protease recognition site. The practitionermatches up the termini of the tubular tissue, and applies adhesiveexternally to the seam where the termini adjoin, and allows the sealantto cure, thereby creating a contiguous tubular tissue. Enzyme isinjected into the location of the substantially solidified sol-gel andthe sol-gel is digested into constituent parts, which are then absorbedby surrounding tissue or removed as part of the systemic body wasteremoval.

Example 7 Prophetic Example of Use of a Sol-Gel Material Having aTransition Temperature at or Below The Body Temperature in a End-To-EndAnastomosis

The aorta of a patient in need of the procedure is clamped proximallyand distally, and subsequently divided and flushed with heparinizedsaline. A sol-gel composition having a transition temperature at orbelow the body temperature, e.g. at about 15° C. to about 30° C., isinjected in a semi-solid or a gel state. The sol-gel composition maycontain about 5% to about 30% of a poloxamer. For example, thecomposition of 17% Poloxamer 407 in water has a transition temperatureof 25° C. to 30° C. as shown in FIG. 7. As such, Poloxamer 407solidifies when injected into the aorta which has a temperature of above30° C. After direct reapproximation by pushing the ends of the aortatogether, the cyanoacrylate adhesive is applied and allowed to cure for60-120 seconds. An appropriate amount of cold sterile saline or ice isapplied to the sited connected to induce the gel change to a liquid. Theclamps are then removed to reestablish blood flow, and the midlineincision is closed in layers with 5-0 vicryl (Ethicon, Inc., Somerset,N.J.) and 4-0 nylon (Ethicon) in a running fashion.

Example 8 An Anastomosis Operation Using a Sol-Gel Composition with TwoPoloxamers

Methods: Rheological studies as described in Example 1 determined theformulation of 17% of poloxamer 407 and 6% of poloxamer 188 (P407/P188)could obtain a phase transition temperature at 42° C. Anastomoses wereperformed on Fisher rat aortas using P407/P188 and bioadhesives (n=30)and 10-0 nylon sutures (n=30). CT angiograms, burst strength assays,histology, and scanning electron microscopy (SEM) were performed atdesignated timepoints. Tissue factor pathway inhibitor (TFPI) ELISA wasperformed on media harvested from human umbilical vein endothelial cells(HUVECs) exposed to heparin and heparinized P407/P188.

Results: The average diameter of the rat aorta used for the end-to-endanastomoses in this study was 2.8 mm, and the average diameter of theiliac vessels used in the end-to-side anastomoses was 1.9 mm. End-to-endanastomoses performed using P407/P188 were completed more efficientlythan the hand-sewn technique (10.0±4.2 min vs. 47.3±5.0 min, p<0.05)with equivalent burst strengths (>1500 mm Hg, p>0.05). Angiogramsdemonstrated equivalent patency, and flow through native aorta,hand-sewn anastomoses, and sutureless anastomoses were not significantlydifferent (26 mL/sec vs. 27 mL/sec vs. 29 mL/sec respectively).Histology and SEM demonstrated less fibrosis in the sutureless groupcompared with the traditional technique. End-to-side anastomosesperformed with the hand-sewn technique had 100% failure rate; however,end-to-side sutureless anastomoses were successful in 33% of operationsperformed (p<0.05). Heparinized poloxamer-induced a significantpercentage increase in secretion of TFPI compared with heparinadministered directly to HUVECs (231.8%, p<0.05) with effects lasting upto 24 hours (125.4%, p<0.05).

The results indicates that P407/P188 can provide an efficient andsustained means of delivering antithrombotic agents, and suturelessanastomoses achieve equivalent patency rates and burst strength withsignificantly less fibrosis. This technology has promising implicationsfor the fields of vascular, cardiothoracic, plastic, and transplantsurgery.

The preceding merely illustrates the principles of the invention. Itwill be appreciated that those skilled in the art will be able to devisevarious arrangements which, although not explicitly described or shownherein, embody the principles of the invention and are included withinits spirit and scope. Furthermore, all examples and conditional languagerecited herein are principally intended to aid the reader inunderstanding the principles of the invention and the conceptscontributed by the inventors to furthering the art, and are to beconstrued as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and embodiments of the invention as well asspecific examples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. The scope of the presentinvention, therefore, is not intended to be limited to the exemplaryembodiments shown and described herein. Rather, the scope and spirit ofpresent invention is embodied by the appended claims.

That which is claimed is:
 1. A method for joining at least twonon-conjoined lumens in a patient which method comprises: (a) placing abiocompatible phase-reversible sol-gel composition in a liquid phase ora gel phase in at least the distal portion of at least one of thelumens, which phase-reversible sol-gel composition is capable of phasetransition from a liquid phase to a gel phase and from the gel phase tothe liquid phase, wherein when the sol-gel composition is placed in thelumen in the liquid phase, a phase transition is induced wherein theliquid phase changes to the gel phase, and wherein the gel phase of thesol-gel composition provides structural support to said portion of thelumen; (b) aligning the lumens; (c) closing the aligned lumens to form aconduit; and (d) removing the sol-gel composition by inducing a phasetransition of the sol-gel composition from the gel phase to the liquidphase thereby establishing flow through the conduit; wherein thephase-transition of the sol-gel composition is triggered by an stimulusselected from a change in temperature, a change in pH, a change in ionicstrength, a change in pressure, a change in electric field, a change inmagnetic field, a change in electron magnetic radiation, a change inlight or ultraviolet light, a change in concentration, a change inosmolarity, and combinations thereof.
 2. The method of claim 1, furthercomprising a step before step (a), which step comprises arresting theflow of body fluid in the lumens.
 3. The method of claim 1, wherein thesol-gel composition is placed in the distal portion of each lumen to bejoined.
 4. The method of claim 1, wherein the sol-gel composition isplaced in the distal portion of a first lumen in a manner in which thesol-gel composition protrudes from the distal portion such that thisprotrusion can be used as a male mating functionality with the distalportion of the second lumen which acts as a female mating functionality.5. The method of claim 1, wherein step (a) comprises: (a1) placing thephase-reversible sol-gel composition in a gel phase inside at least aportion of the distal end of at least one of the lumens in a mannerwhich provides structural support to said portion of the lumen.
 6. Themethod of claim 1, wherein step (a) comprises: (a2) placing thephase-reversible sol-gel composition in a liquid phase inside at least aportion of the distal end of at least one of the lumens; and (a3)inducing a phase transition change in the phase-reversible sol-gelcomposition in the lumen wherein the liquid phase changes to a gel phasewhich provides structural support to said portion of the lumen.
 7. Themethod of claim 1, wherein the sol-gel composition has an elasticmodulus of at least 100 Pascals when in its gel phase.
 8. The method ofclaim 1, wherein the sol-gel composition has an elastic modulus of atleast 8,000 Pascals when in its gel phase.
 9. The method of claim 1,wherein the sol-gel composition is a thermoreversible sol-gel having atransition temperature of from about 0° C. to about 45° C.
 10. Themethod of claim 9, wherein the transition temperature is from about 15°C. to about 35° C.
 11. The method of claim 10, wherein the sol-gelcomposition is removed from the joined lumens by cooling the joinedlumens to a temperature that is below the transition temperature of thesol-gel composition.
 12. The method of claim 11, wherein the cooling isconducted by applying water or an aqueous solution or ice.
 13. Themethod of claim 9, wherein the thermoreversible sol-gel comprises anaqueous solvent and a polymer selected from the group consisting ofpoloxamer 118, poloxamer 188, poloxamer 338, poloxamer 407, Tetronic®1107 and Tetronic® 1307, or a mixture thereof.
 14. The method of claim13, wherein the polymer is present in an amount of about 5% to about 35%by weight.
 15. The method of claim 14, wherein the polymer is present inan amount of about 15% to about 20% by weight.
 16. The method of claim1, wherein the phase-transition of the sol-gel composition is triggeredby a stimulus which comprises a change in ionic strength.
 17. The methodof claim 16, wherein the sol-gel composition is a gel in an environmenthaving an ionic strength higher than the ionic strength of the bodyfluid in the lumen and becomes a liquid in an environment having anionic strength equal to or lower than the ionic strength of the bodyfluid in the lumen.
 18. The method of claim 17, wherein the sol-gelcomposition is placed in at least one of the lumens as a gel, andwherein the sol-gel composition is removed by reducing the ionicstrength to an ionic strength that is equal to the ionic strength of thebody fluid in the lumen with the body fluid thereby inducing the sol-gelcomposition to undergo a phase transition from the gel phase to a liquidphase.
 19. The method of claim 1, wherein the sol-gel composition isremoved by dissolving the sol-gel composition with body fluid.
 20. Themethod of claim 1, wherein joining of the lumens is conducted bysuturing.
 21. The method of claim 1, further comprising a step ofpartially suturing the lumens, where said step is performed beforeand/or after step (a).
 22. The method of claim 1, wherein joining of thelumens is conducted using a biocompatible adhesive.
 23. The method ofclaim 1, wherein joining of the lumens is conducted using laser.